May, 2020, iScience
Solution Phase DNA-Compatible Pictet-Spengler Reaction Aided By Machine Learning Building Block Filtering
The application of machine learning towards DNA encoded library (DEL) technology is lacking despite obvious synergy between these two advancing technologies. Herein, a machine learning algorithm has been developed that predicts the conversion rate for the DNA compatible reaction of a building block with a model DNA-conjugate. We exemplify the value of this technique with a challenging reaction, the Pictet-Spengler, where acidic conditions are normally required to achieve the desired cyclization between tryptophan and aldehydes to provide tryptolines. This is the first demonstration of using a machine learning algorithm to cull potential building blocks prior to their purchase and testing for DNA encoded library synthesis. Importantly, this allows for a challenging reaction, with an otherwise very low building block pass rate in the test reaction, to still be used in DEL synthesis. Furthermore, because our protocol is solution-phase it is directly applicable to standard plate-based DEL synthesis.
April,2020, Organic Letters
opper-Mediated DNA-Compatible One-Pot Click Reactions of Alkynes with Aryl Borates and TMS-N3
We report a DNA-compatible copper-mediated eﬃcient synthesis of 1,2,3-triazoles via a one-pot reaction of aryl borates with TMS-N3 followed by a click cycloaddition reaction. Employing the binuclear macrocyclic nanocatalystCu(II)-βcyclodextrin, the reactions were performed under mild conditions with high conversions and wide functional group tolerance. We also demonstrate the reaction application toward a one-pot DNAcompatible intramolecular macrocyclization. Our optimized reaction protocol results in no signiﬁcant DNA damage as judged by qPCR analysis and Sanger sequencing data.
May, 2020, Organic Letters
DNA Compatible Intermolecular Wittig Oleﬁnation for the Construction of α, β‑Unsaturated Carbonyl Compounds
A robust DNA-compatible Wittig reaction mediated by PPh2CH3 has been validated for DNA-conjugated αchloroacetamides with aldehydes and, alternatively, DNA-conjugated aldehydes with α-halo acetamides or ketones. Further, 2aminopyridines were acylated with α-chloroacetyl chloride and then reacted with DNA-conjugated aldehydes. Lastly, a pilot library employing our optimized Wittig reaction protocol was synthesized. The ability to generate α,β-unsaturated carbonyl compounds may be particularly useful for the design of DNA-encoded libraries capable of covalently interacting with protein targets.
Aug, 2020, Bioconjugate Chemistry
DNA-Compatible Copper-Catalyzed Oxidative Amidation of Aldehydes with Non-Nucleophilic Arylamines
We report a DNA-compatible protocol for synthesizing amides from DNA-bound aldehydes and non-nucleophilic arylamines including aza-substituted anilines, 2-aminobenzimidazoles, and 3-aminopyrazoles. The reactions were carried out at room temperature and provided reasonable conversions and wide functional group compatibility. The reactions were also successful when employing aryl and aliphatic aldehydes. In addition, qPCR and NGS data suggested no negative impact on DNA integrity after the copper-mediated oxidative amidation reaction.
March,2020,Biochemical and Biophysical Research Communications
Palladium-mediated Suzuki-Miyaura Cross-Coupling Reaction of Potassium Boc-protected aminomethyltriﬂuoroborate with DNAConjugated aryl bromides for DNA-Encoded chemical librarysynthesis
A mild reaction for DNA-compatible, palladium promoted Suzuki-Miyaura cross-coupling reaction of potassium Boc-protected aminomethyltriﬂuoroborate with DNA-conjugated aryl bromides has been developed efﬁciently. This novel DNA encoded chemistry reaction proceeded well with a wide range of functional grouptolerance, including aryl bromides and heteroaryl bromides. Further, the utility our DNA conjugated aminomethylated arene products is demonstrated by reaction with various types of reagents (including amide formation with carboxylic acids, alkylation with aldehydes, and carbamoylation with amines) as would be desired for the production of a DNA encoded library.
A Strategy for the Synthesis of Sulfonamides on DNA
An eﬃcient method is reported to synthesize sulfonamides on DNA from sulﬁnic acids or sodium sulﬁnates and amines in the presence of iodine under mild conditions. This method demonstrates a major expansion of scope of sulfonamide formation on DNA through the utilization of a novel sodium carbonate−sodium sulﬁnate bifunctional reagent class.
January,2017,Current Drug Discovery Technologies
Compound Libraries: Recent Advances and Their Applications in Drug Discovery
Hit identification is the starting point of small-molecule drug discovery and is therefore very important to the pharmaceutical industry. One of the most important approaches to identify a new hit is to screen a compound library using an in vitro assay. High-throughput screening has made great contributions to drug discovery since the 1990s but requires expensive equipment and facilities, and its success depends on the size of the compound library. Recent progress in the development of compound libraries has provided more efficient ways to identify new hits for novel drug targets, thereby helping to promote the development of the pharmaceutical industry, especially for firstin-class drugs.